Chapter Two - Hematopoietic Stem Cell Development: An Epigenetic Journey
Introduction
Hematopoiesis is the highly dynamic process sustaining the life-long production of blood, one of the most highly regenerative tissues. All hematopoietic lineages—including erythrocytes, platelets, myelocytes, and lymphocytes—derive from a pool of multipotent hematopoietic stem cells (HSCs) residing in the bone marrow (BM). HSCs are characterized by their ability to both self-renew and differentiate: while self-renewal guarantees the life-long maintenance of the stem cell compartment, differentiation involves the sequential steps leading to the production of mature blood cells.
Multilineage hematopoietic stem and progenitor cells (HSPCs) emerge early in ontogeny. After a first wave of primitive blood cells arising from the mesoderm, multilineage HSCs start to emerge from the extraembryonic yolk sac and placenta, followed by the aorta-gonad-mesonephros (AGM) region of the embryo (Moore and Metcalf, 1970, Samokhvalov et al., 2007). As gestation progresses, HSCs migrate to the fetal liver, which becomes the major site of definitive hematopoiesis until the latest stages of embryonic development. Shortly before birth, blood cell production emerges in the BM, the final and predominant site of hematopoiesis throughout adulthood (Fig. 2.1A) (Lux et al., 2008). In adult mammals, definitive hematopoiesis is sustained by a pool of long-term HSCs (LT-HSCs), from which short-term HSCs (ST-HSCs) and multipotent progenitors (MPPs) are derived; these stem and progenitor cells present a progressively decreased self-renewal potential, but still hold a multipotential differentiation capacity. Downstream of MPPs are lineage-restricted progenitors, responsible for generating a large pool of terminally differentiated cells eventually released into the peripheral blood (Fig. 2.1B).
Several factors, both extrinsic and intrinsic, regulate the progression of HSCs through the different phases of their development. Cell-extrinsic cues are provided by the stem cell niche and include cytokines, growth factors, chemokines, oxygen tension, and nutrients (Smith and Calvi, 2013, Suda et al., 2011, Wilson and Trumpp, 2006). These signals merge into a network of intrinsic regulators, comprising signaling pathways, transcription factors, and epigenetic marks. By controlling chromatin conformations and accessibility, epigenetic mechanisms tune the expression of genes involved in HSC development and help orchestrate the balance between stemness and lineage commitment. Over the past decade, analyses of knockout (KO) mice have contributed to unveiling a number of genes vital for HSC development and function (Rossi et al., 2012), including, but not limited to: DNA-methylating enzymes, Polycomb-Group (PcG) complexes, histone modifiers, and factors involved in microRNA synthesis (summarized in Table 2.1, Table 2.2, Table 2.3, Table 2.4). Deletion of these genes in KO mice has been associated with a variety of phenotypes—from hematopoietic failure and repopulation defects to hyperproliferation and leukemia—reinforcing the hypothesis that epigenetic marks concur to mold developmental programs in HSCs. In this review, we will illustrate how epigenetic regulators contribute to the different stages of HSC development—from their embryonic emergence to adult life—focusing on the mechanisms that contribute to HSC self-renewal, lineage commitment, aging, and leukemogenesis.
Section snippets
Principles of Epigenetic Regulation
Epigenetic marks include DNA methylation, covalent histone modification, and chromatin remodeling. In addition to these mechanisms, microRNAs and long noncoding RNAs (lncRNAs) have recently emerged as important regulators of transcriptional and epigenetic programs, playing a pivotal role in early development, lineage specification, and differentiation. In this review, we will focus mainly on DNA and chromatin modifications; for a detailed description of microRNA and lncRNA in hematopoietic
DNA methylation
The importance of proper DNA methylation throughout mammalian development is made evident by germline deletion of Dnmts: Dnmt1-null mice die at gastrulation (Li, Bestor, & Jaenisch, 1992), Dnmt3b-null mice die at roughly E9.5, and Dnmt3a-null mice die at roughly 3 weeks of age (Okano, Bell, Haber, & Li, 1999). Additional research has shown DNA methylation to be remarkably fluid early in development: present in gametes, nearly completely erased in the early morula, and then largely reestablished
Role of Epigenetic Regulators in Hematopoietic Malignancies
Despite the intense regulatory activity presiding over hematopoietic homeostasis, aberrant clones may arise from HSPCs, giving rise to a pool of malignant cells characterized by unrestrained proliferation and/or abnormal differentiation patterns. Previously viewed as exquisitely genetic diseases, hematopoietic malignancies have now emerged as a deviant developmental process. As such, leukemogenesis can be ascribed to the abnormal activity of the same regulatory mechanisms modulating
Conclusions
Over the past decade, the understanding of the molecular mechanisms presiding over epigenetic regulation has greatly improved. Not only have epigenetic marks emerged as pivotal regulators of the different stages of hematopoietic development but they also appear to be key players in leukemogenesis. In the future, the ability to manipulate the epigenetic pattern of genes involved in hematological diseases is expected to provide a huge array of new therapeutic approaches for leukemia. Along this
Acknowledgments
The authors would like to thank members of the Goodell lab for helpful discussions. The authors are supported by grants DK092883, 5T32HL092332, 1RC2AG036562-01, the Samuel Waxman Foundation, and the Cancer Prevention and Research Institute of Texas (CPRIT RP110028). L. R. was supported by the Italian Leukemia and Lymphoma Association, section of Bologna (BolognaAIL).
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These authors contributed equally to this work